Targeting FTO shows therapeutic potential in esophageal squamous cell carcinoma by modulating microRNA biogenesis

N⁶-methyladenosine (m⁶A) RNA modification is a pivotal post-transcriptional regulator of RNA metabolism and cancer progression. Fat mass and obesity-associated protein (FTO), an m⁶A demethylase, has emerged as a potent oncogenic driver across multiple malignancies. In this study, we demonstrate that FTO directly demethylates the primary transcripts of the miR-200b/a/429 cluster, thereby impeding DGCR8-mediated recognition and processing. The ensuing reduction in mature tumor-suppressive miR-200b/a/429 relieves repression of a suite of downstream targets intimately linked to metastasis and cell proliferation, ultimately accelerating tumor growth and lymph-node dissemination in esophageal squamous cell carcinoma (ESCC). Pharmacologic inhibition of FTO restores miR-200b/a/429 cluster expression and partially rescues the oncogenic phenotype elicited by FTO overexpression. Collectively, our findings uncover a previously unrecognized FTO-m⁶A-miR-200b/a/429 axis that propels ESCC progression and highlight FTO as a promising therapeutic target for patients with ESCC.